IL-17-driven mechanisms for tumor progression and resistance to therapies

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Project Summary While the relationship between chronic inflammation and cancer is well recognized, knowledge of the cellular and molecular mechanisms that link these processes continues to evolve. Intratumoral interleukin 17A (IL-17) levels are associated with poor prognosis for a variety of solid tumors in human. The overall goal of this application is to investigate the mechanisms of IL-17-mediated cancer progression, focusing on tumor responses to anti-cancer therapies. Our recent preliminary data revealed that IL-17 engages both cancer cells and tumor microenvironment to synergistically promote cancer progression. Firstly, work supported by this award identified a non-canonical IL-17-induced EGFR-mediated ERK5 signaling cascade critical for tumorigenesis. Our new preliminary study revealed an Lrig1+ stem-like tumor cell population in squamous cell carcinoma that are highly responsive to IL-17 with EGFR-ERK5 activation. Transcriptomic profiling revealed a link between IL-17-ERK5 axis in human and mouse Lrig1+ stem-like tumor cells with NRF2-mediated antioxidation and Wnt5a-dependent induction of stemness. Lineage tracing showed that IL-17 rendered these Lrig1+ stem-like tumor cells resistance to chemotherapy, which were also enriched by anti-PD1 treatment. Secondly, we found that canonical IL-17 signaling operates in both tumor cells and stromal cells to dictate a tumor-promoting and immune suppressive environment. In tumor cells, IL-17 synergizes with other inflammatory cytokines to orchestrate an intratumoral cancer promoting inflammation via the induction of specific effector molecules. In cancer-associated fibroblasts, IL-17 signaling helps to establish an immune exclusion zone to prevent the infiltration of CD8+ T cells. Deletion of IL-17R in CAFs rendered these tumors sensitive to immune therapy. Based on these observations, we hypothesize that canonical and non-canonical IL-17 signaling in cancer cells and CAFs coordinately drive cancer progression and resistance to therapies. To test this hypothesis, we will (1) Investigate how IL-17R-EGFR axis in Lrig1+ stem-like tumor cells renders resistance to anti-cancer therapies; (2) Elucidate the mechanism by which IL-17 shapes the pro-tumor immune exclusive tumor microenvironment. Program Interactions: This Project will be critically informed by and also provide necessary information to the other Projects in the Program at multiple levels. Project 1 and Project 2 will investigate the antagonistic interplay between IFNβ and TGFβ in cancer cell differentiation. Informed by those studies, we will determine whether STING-induced IFNβ can be used to eradicate Lrig1+ cells to improve responses to anti-cancer therapies. We will take advantage of the Animal Model, Immunotyping and Analytics Core B to standardize our in vivo analyses, including preclinical assessment of cancer therapeutics and characterization of the tumor microenvironment (TME). Statistical analyses will be performed by Program Biostatistician Dr. Bo Hu and Program Bioinformatician Dr. Fulai Jin (Core B).